The concept of neutron capture therapy was first proposed by Locher in 1936 as a means for treating cancer. In this therapy, a capture agent with a large neutron cross section is transported to and selectively accumulated in tumor cells. Upon irradiation by low-energy neutrons, the capture agent localized in the tumor "absorbs" the neutrons and emits highly ionizing and localized radiation which is lethal to cells. See in this regard:
Locher, G. I. "Biological Effects of Therapeutic Possibilities of Neutrons", American Journal of Roentgenology, Vol. 36, No. 1 (1936). PA1 Hatanaka, H., "Boron Uptake by Human Brian Tumors and Quality Control of Boron Compounds," in "Boron-Neutron Capture Therapy of Tumors," edited by H. Hatanaka, Nishimura Co., Ltd., p. 77 (1986) PA1 Hatanaka, H., "Clinical Experience of Boron-Neutron Capture Therapy for Gliomas-A Comparison with Conventional Chemo-Immuno-Radiotherapy," in Boron Neutron Capture Therapy for Tumors, edited by H. PA1 Joel, D. D., et al., "Pharmacokinetics and Tissue Distribution of the Sulfhydryl Boranes (Monomer and Dimer) in Glioma-Bearing Rats," Strahlenther, Onkol., Vol. 165, p 167 (1989) PA1 Coderre, J. A., et al., "Selective Delivery of Boron by the Melanin Precursor Analogue p-Boronphenylalanine to Tumors Other than Melanoma," Cancer Research 50, p 138 (January 1990)
Locher's concept for neutron capture therapy has progressed over the past 50 years to the identification of suitable (1) capture agents, (2) pharmaceuticals to carry the agents to and concentrate the agents in the tumors and (3) neutron energy spectra, irradiation flux and irradiation time appropriate for effective cancer therapy. In particular, boron-10 has been found to be well suited as a targeting agent for neutron capture therapy. In this reaction, owing to its non-toxicity and high capture cross section, a low energy neutron captured by boron-10 yields two charged particles, an alpha particle and a lithium ion, with sufficient energy to kill cells, yet the charged particles travel only about 10 microns-about the diameter of an average cell. As a result, the lethality of the neutron capture is limited to the cells adjacent the location of boron atoms and does not affect healthy tissues nearby.
Particularly since the early 1960's, there has been significant progress in the development of boron containing targeting agents. One compound, polyhedral borane (NA.sub.2 B.sub.12 H.sub.11 SH, abbreviated as "BSH") has been used with some success in human trials conducted by Dr. Hiroshi Hatanaka at Teikyo University in Tokyo. Using this compound, Hatanaka has reported tumor to blood concentration ratios of boron-10 of up to 2, and with an average boron-10 concentration of 26.3 microgram/gram in the tumor and has treated about 100 patients. Using a reactor source of thermal neutrons, Hatanaka has achieved a three-fold increase in patient survival time. See:
Hatanaka, Nishimura Co., Ltd., p. 349 (1986). Several new boron-10-containing compounds have been developed and some of them have been tested with animals. Promising compounds which have been tested in tumor-bearing animals include NA.sub.4 B.sub.24 H.sub.22 S.sub.2 (or BSSB, the dimer of BSH), and a boronated amino acid called p-boronphenylalanine (or BPA). Other new antibodies, nucleosides, low-density lipoprotein, and liposomes have been investigated. Among them, porphyrins have already shown therapeutic efficacy in treating tumor-bearing animals with NCT. While BSH has shown therapeutic efficacy in human glioma, BPA and prophyrin are the two prime candidates which may eventually make NCT a widely used modality in treating human malignant tumors other than glioma. See the following publications in connection with the above.
In addition to the progress made in the development of boron-10 targeting agents, significant advances have been made in the field of accelerators as an alternative to the use of reactors. Accelerator technology currently allows the generation of a proton beam of the requisite energy level and intensity (i.e., beam current). It also is known that if a lithium target is bombarded with a proton beam of the requisite energy level and intensity, a neutron beam can be produced. However, in order to be useful for boron neutron capture therapy, this neutron beam must be moderated in order to lower the energy level of the neutrons from the 100 keV to 800 keV range to the 1 eV to 10 keV range. Moderator systems for reducing the neutron beam energy levels to the desired range have been designed and experimentally proven, and utilize materials such as beryllium oxide, aluminum oxide and heavy water (i.e., D.sub.2 O).
However, cooling systems heretofore employed for the removal of very high heating loads and high heat fluxes have been limited. One approach uses the latent heat of vaporization of lithium in order to remove the heat generated by the bombarding proton beam by boiling the lithium target. This scheme for target cooling has two limitations. First, the chamber containing vaporized lithium must be continuous with the evacuated channel leading to the proton accelerator. As a result, unwanted lithium vapor leakage into the accelerator chamber is unavoidable. Second, in order to transfer the requisite amount of heat, the lithium target must be operated at temperatures above 900.degree. C., a requirement which presents significant operational and safety problems for use in hospital-based therapy sites.
Another approach to the generation of neutrons for neutron capture therapy is described in U.S. Pat. No. 4,666,651. The approach utilizes a neutron generator to generate charged particles having an energy of at least 15 MeV. These particles are directed at a lithium deuteride target which is cooled by the circulation of gas which is chemically non-reactive with the lithium deuteride target. However, as the high heat fluxes associated with the generation of high intensity neutron beams preferred for neutron capture therapy (viz. 500 to 1500 watts/cm.sup.2), the use of gas cooling is limited due to high target temperatures, high exit gas temperatures and large gas flow rates.
Previous target cooling systems have included the use of liquid-cooled stationary targets as illustrated in U.S. Pat. No. 4,599,515 by Whittemore, and U.S. Pat. No. 4,192,998 by Azam. However, the high heat fluxes (500 to 1500 watts/cm.sup.2) associated with the above high intensity neutron irradiation systems exceed the heat dissipation capability of existing stationary, liquid-cooled targets. As a consequence, preferred target materials such as lithium cannot be effectively used as the target temperature where high heat fluxes greatly exceed the melting point resulting in unwanted evaporation of the target (e.g., lithium). Others have attempted to increase the effectiveness of target cooling by rotating the target material (e.g., beryllium or lithium) relative to a stationary beam of protons or deuterons. (See U.S. Pat. No. 4,582,667 by Bauer; U.S. Pat. No. 4,360,495 by Bauer; U.S. Pat. No. 4,112,306 by Nunan; and U.S. Pat. No. 4,090,086 by Cranberg.) However, all such targets have been designed for the production of high energy neutrons using an incident beam of high energy ions (e.g., protons or deuterons), such neutrons having energies in the range from several hundred keV to several GeV and higher. As a consequence of the objective of producing high energy neutrons, target cooling systems have not excluded hydrogenous coolant fluids (e.g., water) from the forward beam of neutrons since small layers of hydrogenous materials will not result in a significant attenuation of the neutron beam produced. In the case of Bauer (U.S. Pat. Nos. 4,582,667 and 4,360,495), the target material forms a matrix through which a liquid coolant flows.
Also, earlier target and target cooling designs provide no technique for containment of low melting temperature target materials such as lithium. In addition, those methods do not consider the importance of maintaining rotational speed of rotating targets on the containment of target materials when heated to temperatures above their melting point.